Spectral and phase-amplitude coupling signatures in human deep brain oscillations during propofol-induced anaesthesia.

BACKGROUND: Both the cerebral cortex and subcortical structures play important roles in consciousness. Some evidence points to general anaesthesia-induced unconsciousness being associated with distinct patterns of superficial cortical electrophysiological oscillations, but how general anaesthetics influence deep brain neural oscillations and interactions between oscillations in humans is poorly understood. METHODS: Local field potentials were recorded in discrete deep brain regions, including anterior cingulate cortex, sensory thalamus, and periaqueductal grey, in humans with implanted deep brain electrodes during induction of unconsciousness with propofol. Power-frequency spectra, phase-amplitude coupling, coherence, and directed functional connectivity analysis were used to characterise local field potentials in the awake and unconscious states. RESULTS: An increase in alpha (7-13 Hz) power and decrease in gamma (30-90 Hz) power were observed in both deep cortical (ACC, anterior cingulate cortex) and subcortical (sensory thalamus, periaqueductal grey) areas during propofol-induced unconsciousness. Robust alpha-low gamma (30-60 Hz) phase-amplitude coupling induced by general anaesthesia was observed in the anterior cingulate cortex but not in other regions studied. Moreover, alpha oscillations during unconsciousness were highly coherent within the anterior cingulate cortex, and this rhythm exhibited a bidirectional information flow between left and right anterior cingulate cortex but stronger left-to-right flow. CONCLUSION: Propofol increases alpha oscillations and attenuates gamma oscillations in both cortical and subcortical areas. The alpha-gamma phase-amplitude coupling and the functional connectivity of alpha oscillations in the anterior cingulate cortex could be specific markers for loss of consciousness.

The Cognitive Role of the Globus Pallidus interna; Insights from Disease States.

The motor symptoms of both Parkinson's disease and focal dystonia arise from dysfunction of the basal ganglia, and are improved by pallidotomy or deep brain stimulation of the Globus Pallidus interna (GPi). However, Parkinson's disease is associated with a greater degree of basal ganglia-dependent learning impairment than dystonia. We attempt to understand this observation in terms of a comparison of the electrophysiology of the output of the basal ganglia between the two conditions. We use the natural experiment offered by Deep Brain Stimulation to compare GPi local field potential responses in subjects with Parkinson's disease compared to subjects with dystonia performing a forced-choice decision-making task with sensory feedback. In dystonic subjects, we found that auditory feedback was associated with the presence of high gamma oscillations nestled on a negative deflection, morphologically similar to sharp wave ripple complexes described in human rhinal cortex. These were not present in Parkinson's disease subjects. The temporal properties of the high gamma burst were modified by incorrect trial performance compared to correct trial performance. Both groups exhibited a robust low frequency response to 'incorrect' trial performance in dominant GPi but not non-dominant GPi at theta frequency. Our results suggest that cellular processes associated with striatum-dependent memory function may be selectively impaired in Parkinson's disease even if dopaminergic drugs are administered, but that error detection mechanisms are preserved.

Deep brain stimulation for tremor resulting from acquired brain injury.

OBJECTIVES: To evaluate the efficacy of deep brain stimulation (DBS) in the treatment of tremor resulting from acquired brain injury (ABI). METHODS: A series of eight consecutive patients with post-ABI tremor were treated with DBS of the ventro-oralis posterior (VOP)/zona incerta (ZI) region, and subsequently underwent blinded assessments using Bain's tremor severity scale. RESULTS: VOP/ZI DBS produced a mean reduction in tremor severity of 80.75% based on Bain's tremor severity scale, with significant reductions in all five component tremor subscores: rest, postural, kinetic, proximal and distal. No adverse neurological complications were reported, although one patient experienced exacerbation of pre-existing gait ataxia. CONCLUSION: VOP/ZI stimulation is demonstrated here to be an effective and safe approach for the treatment of post-ABI tremor in the largest series published at the time of writing.

Long-term outcome of deep brain stimulation in generalised dystonia: a series of 60 cases.

BACKGROUND: There is solid evidence of the long term efficacy of deep brain stimulation of the globus pallidus pars interna in the treatment of generalised dystonia. However there are conflicting reports concerning whether certain subgroups gain more benefit from treatment than others. We analysed the results of a series of 60 cases to evaluate the effects of previously proposed prognostic factors including dystonia aetiology, dystonia phenotype, age at onset of dystonia, and duration of dystonia prior to treatment. METHODS: 60 patients with medically intractable primary or secondary generalised dystonia were treated with deep brain stimulation of the globus pallidus pars interna during the period 1999-2010 at the Department of Neurosurgery in Oxford, UK. Patients were assessed using the Burke-Fahn-Marsden (BFM) Dystonia Rating Scale prior to surgery, 6 months after implantation and thereafter at 1 year, 2 years and 5 years follow-up. RESULTS: The group showed mean improvements in the BFM severity and disability scores of 43% and 27%, respectively, by 6 months, and this was sustained. The results in 11 patients with DYT gene mutations were significantly better than in non-genetic primary cases. The results in 12 patients with secondary dystonia were not as good as those seen in non-genetic primary cases but there remained a significant beneficial effect. Age of onset of dystonia, duration of disease prior to surgery, and myoclonic versus torsional disease phenotype had no significant effect on outcome. CONCLUSIONS: The aetiology of dystonia was the sole factor predicting a better or poorer outcome from globus pallidus pars interna stimulation in this series of patients with generalised dystonia. However even the secondary cases that responded the least well had a substantial reduction in BFM scores compared with preoperative clinical assessments, and these patients should still be considered for deep brain stimulation.

Thalamic deep brain stimulation for post-traumatic neuropathic limb pain: Efficacy at five years' follow-up and effective volume of activated brain tissue.

Chronic neuropathic pain affects 7%-10% of the population. Deep brain stimulation (DBS) has shown variable but promising results in its treatment. This study prospectively assessed the long-term effectiveness of DBS in a series of patients with chronic neuropathic pain, correlating clinical results with neuroimaging. Sixteen patients received 5 years' post-surgical follow-up in a single center. Six had phantom limb pain after amputation and 10 had deafferentation pain after traumatic brachial plexus injury. Patient-reported outcome measures were completed before and after surgery, using VAS, UWNPS, BPI and SF-36 scores. Neuroimaging evaluated electrode location and effective volumes of activated tissue (VAT). Two subgroups were created based on the percentage of VAT superimposed upon the ventroposterolateral thalamic nucleus (eVAT), and clinical outcomes were compared. Analgesic effect was assessed at 5 years and compared to preoperative pain, with an improvement on VAS of 76.4% (p=0.0001), on UW-NPS of 35.2% (p=0.3582), on BPI of 65.1% (p=0.0505) and on SF-36 of 5% (p=0.7406). Eight patients with higher eVAT showed improvement on VAS of 67.5% (p=0.0017) while the remaining patients, with lower eVAT, improved by 50.6% (p=0.03607). DBS remained effective in improving chronic neuropathic pain after 5 years. While VPL-targeting contributes to success, analgesia is also obtained by stimulating surrounding posterior ventrobasal thalamic structures and related spinothalamocortical tracts.

Neuroablative surgical treatments for pain due to cancer.

Cancer pain is common and challenging to manage - it is estimated that approximately 30% of cancer patients have pain that is not adequately controlled by analgesia. This paper discusses safe and effective neuroablative treatment options for refractory cancer pain. Current management of cancer pain predominantly focuses on the use of medications, resulting in a relative loss of knowledge of these surgical techniques and the erosion of the skills required to perform them. Here, we review surgical methods of modulating various points of the neural axis with the aim to expand the knowledge base of those managing cancer pain. Integration of neuroablative approaches may lead to higher rates of pain relief, and the opportunity to dose reduce analgesic agents with potential deleterious side effects. With an ever-increasing population of cancer patients, it is essential that neurosurgeons maintain or train in these techniques in tandem with the oncological multi-disciplinary team.

Perioperative seizures following deep brain stimulation in patients with multiple sclerosis.

Following a total of 386 deep brain stimulation (DBS) procedures in Oxford, only two seizures have been recorded in the peri-operative period. Both patients had MS and underwent thalamic DBS for tremor and these 2 cases are presented here. The incidence of peri-operative seizures in MS patients undergoing DBS procedures is more than 8-fold greater than that expected for patients undergoing DBS procedures. Further experience with DBS procedures in MS patients is needed to determine whether there is a role for peri-operative anticonvulsants in these patients.

Local field potentials reveal a distinctive neural signature of cluster headache in the hypothalamus.

Cluster headache (CH) is a debilitating neurovascular condition characterized by severe unilateral periorbital head pain. Deep brain stimulation of the posterior hypothalamus has shown potential in alleviating CH in its most severe, chronic form. During surgical implantation of stimulating macroelectrodes for cluster head pain, one of our patients suffered a CH attack. During the attack local field potentials displayed a significant increase in power of approximately 20 Hz. To the authors' knowledge, this is the first recorded account of neuronal activity observed during a cluster attack. Our results both support and extend the current literature, which has long implicated hypothalamic activation as key to CH generation, predominantly through indirect haemodynamic neuroimaging techniques. Our findings reveal a potential locus in CH neurogenesis and a potential rationale for efficacious stimulator titration.

Pre-operative DTI and probabilisitic tractography in four patients with deep brain stimulation for chronic pain.

This study aimed to examine, using diffusion tensor imaging (DTI), differences in electrode placement in four patients undergoing deep brain stimulation for chronic neuropathic pain of varying aetiology. A pre-operative DTI was obtained for each patient, who was then implanted with deep brain stimulation electrodes in the periventricular/periaqueductal grey area with good pain relief. Using seeds from the postoperative MRI scan, probabilistic tractography was performed from the pre-operative DTI.

The anatomy and localization of the pedunculopontine nucleus determined using probabilistic diffusion tractography [corrected].

Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) has recently been shown to effectively ameliorate medically intractable axial symptoms of Parkinson's disease (PD). The effects of DBS are not limited to the targeted structure, but will affect the distributed anatomical networks to which the target structure belongs. Therefore, understanding the anatomical connections of the PPN will help elucidate treatment effects. Furthermore, establishing the topography of cortical and sub-cortical connections of the PPN in the human brain could aid accurate targeting of critical pathways in DBS. This article summarizes the connections of the PPN and the distribution of these connections within this nucleus (topography) as previously determined using diffusion tensor imaging (DTI) in healthy human volunteers and in a primate Macaca mulatta brain. These findings highlight DTI as a useful tool for surgical targeting for DBS of the PPN, and also show that DTI can be used to accurately probe the anatomy of the human and monkey brain in vivo.

Awake stereotactic brainstem biopsy via a contralateral, transfrontal, transventricular approach.

The authors describe a novel approach to stereotactic biopsy of lesions of the lateral pons and medial cerebellar peduncle, and its diagnostic success without morbidity. A contralateral approach laterally expands the accessible infratentorial area. It may also confer a theoretical reduction in neurological deficit with passage through non-dominant right hemisphere.

Deep brain stimulation of the pedunculopontine nucleus in Parkinson's disease. Preliminary experience at Oxford.

Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) is a novel neurosurgical therapy developed to address symptoms of gait freezing and postural instability in Parkinson's disease and related disorders. Here, we summarize our non-human primate and neuroimaging research of relevance to our surgical targeting of the PPN. We also describe our clinical experience of PPN DBS with greatest motor improvements achieved by stimulation at low frequencies.

Thalamic Directional Deep Brain Stimulation for tremor: Spend less, get more.

BACKGROUND: Directional Deep Brain Stimulation (D-DBS) allows axially asymmetric electrical field shaping, away from structures causing side-effects. However, concerns regarding the impact on device lifespan and complexity of the monopolar survey have contributed to sparing use of these features. OBJECTIVE: To investigate whether chronically implanted D-DBS systems can improve the therapeutic window, without a negative impact on device lifespan, in thalamic deep brain stimulation (DBS). METHODS: We evaluated stable outcomes of initial programming sessions (4-6 weeks post-implantation) retrospectively in 8 patients with drug-resistant disabling tremor syndromes. We assessed the impact of directional stimulation on the Therapeutic Window (TW), Therapeutic Current Strength (TCS), tremor scores, disability scores and total electrical energy delivered. Finally, we performed Volume of Tissue Activation (VTA) modelling, based on a range of parameters. RESULTS: We report significant gains in TW (91%) and reductions in TCS (31%) with stimulation in the best direction compared to best omnidirectional stimulation alternative. Tremor and ADL scores improvements remained unchanged at six months. There was no increase in averaged IPG power consumption (there is a 6% reduction over the omnidirectional-only alternative). Illustrative VTA modelling shows that D-DBS achieves 85% of the total activation volume at just 69% of the stimulation amplitude of non-directional configuration. CONCLUSIONS: D-DBS can improve the therapeutic window over non-directional DBS, leading to significant reduction in disability that may be sustained without additional reprogramming visits. When averaged across the cohort, power output and predicted device lifespan was not impacted by the use of directional stimulation in this study.

EFNS guidelines on neurostimulation therapy for neuropathic pain.

Pharmacological relief of neuropathic pain is often insufficient. Electrical neurostimulation is efficacious in chronic neuropathic pain and other neurological diseases. European Federation of Neurological Societies (EFNS) launched a Task Force to evaluate the evidence for these techniques and to produce relevant recommendations. We searched the literature from 1968 to 2006, looking for neurostimulation in neuropathic pain conditions, and classified the trials according to the EFNS scheme of evidence for therapeutic interventions. Spinal cord stimulation (SCS) is efficacious in failed back surgery syndrome (FBSS) and complex regional pain syndrome (CRPS) type I (level B recommendation). High-frequency transcutaneous electrical nerve stimulation (TENS) may be better than placebo (level C) although worse than electro-acupuncture (level B). One kind of repetitive transcranial magnetic stimulation (rTMS) has transient efficacy in central and peripheral neuropathic pains (level B). Motor cortex stimulation (MCS) is efficacious in central post-stroke and facial pain (level C). Deep brain stimulation (DBS) should only be performed in experienced centres. Evidence for implanted peripheral stimulations is inadequate. TENS and r-TMS are non-invasive and suitable as preliminary or add-on therapies. Further controlled trials are warranted for SCS in conditions other than failed back surgery syndrome and CRPS and for MCS and DBS in general. These chronically implanted techniques provide satisfactory pain relief in many patients, including those resistant to medication or other means.

The periaqueductal grey area and the cardiovascular system.

In this chapter, we report that blood pressure can be increased or decreased depending on whether an electrode is in ventral or dorsal PAG. We also describe that it is theoretically possible to treat orthostatic hypotension. These are exciting developments not only because they provide an example of direct translational research from animal research to humans but also because they highlight a potential for future clinical therapies. The control of essential hypertension without drugs is attractive because of the side effects of medication such as precipitation of heart failure [10]. Similarly, drug treatment of orthostatic hypotension cannot differentiate between the supine and standing positions and can therefore lead to nocturnal hypertension [22, 29]. A stimulator could be turned off at night or contain a mercury switch that reacts to posture.

Deep brain stimulation for neuropathic pain.

Deep brain stimulation (DBS) for pain was one of the earliest indications for the therapy. This study reports the outcome of DBS of the sensory thalamus and the periventricular and peri-aqueductal grey area (PVG/PAG) complex for different intractable neuropathic pain syndromes. Forty-seven patients (30 males and 17 females) were selected for surgery; they were suffering from any of the following types of pain: post-stroke neuropathic pain, phantom limb pain, post-herpetic neuralgia, anaesthesia dolorosa, brachial plexus injury and neuropathic pain secondary to neural damage from a variety of causes. Of the 47 patients selected for trial stimulation, 38 patients proceeded to permanent implantation. Patients suffering from post-stroke pain were the most likely to fail trial stimulation (33%), in contrast to individuals with phantom limb/post-brachial plexus injury pain and anaesthesia dolorosa, all of whom underwent permanent implantation. PVG stimulation alone was optimal in 17 patients (53%), whilst a combination of PVG and thalamic stimulation produced the greatest degree of analgesia in 11 patients (34%). Thalamic stimulation alone was optimal in 4 patients (13%). DBS of the PVG alone was associated with the highest degree of pain alleviation, with a mean improvement of 59% (p <0.001) and a > or =50% improvement in 66% of patients. Post-stroke pain responds in 70% of patients. We conclude that the outcomes of surgery appear to vary according to aetiology, but it would appear that the effects are best for phantom limb syndromes, head pain and anaesthesia dolorosa.

Connectivity of an effective hypothalamic surgical target for cluster headache.

The purpose of this study was to look at the connectivity of the posterior inferior hypothalamus in a patient implanted with a deep brain stimulating electrode using probabilistic tractography in conjunction with postoperative MRI scans. In a patient with chronic cluster headache we implanted a deep brain stimulating electrode into the ipsilateral postero-medial hypothalamus to successfully control his pain. To explore the connectivity, we used the surgical target from the postoperative MRI scan as a seed for probabilistic tractography, which was then linked to diffusion weighted imaging data acquired in a group of healthy control subjects. We found highly consistent connections with the reticular nucleus and cerebellum. In some subjects, connections were also seen with the parietal cortices, and the inferior medial frontal gyrus. Our results illustrate important anatomical connections that may explain the functional changes associated with cluster headaches and elucidate possible mechanisms responsible for triggering attacks.

Deep brain stimulation: a new treatment for hypertension?

We report a 61-year-old hypertensive man who underwent deep brain stimulation of the periventricular/periaqueductal grey area for the relief of chronic neuropathic pain affecting his oral cavity and soft palate. During intraoperative stimulation, we were able to modulate his blood pressure up or down, depending on electrode location. This is the first evidence that hypertension could be effectively treated with electrical stimulation of the midbrain.

Parkinson's disease and primate research: past, present, and future.

Scientific research involving non-human primates has contributed towards many advances in medicine and surgery. This review discusses its role in the progress made towards our understanding of Parkinson's disease and its treatment. Established medical treatments like dopamine agonists continue to need primate models to assess their efficacy, safety, and mechanism of action. The recently developed treatment of deep brain stimulation of the subthalamic nucleus required validation in primates before entering the clinic. Controversies surrounding future treatments such as gene therapy show the need for properly evaluated preclinical research using appropriate animal models before progression to clinical trials. Research on primates has played--and continues to play--a crucial part in deepening our understanding of Parkinson's disease, improving current therapies, and developing new treatments that are both safe and effective. In animal research, the "three Rs" of humane technique--reduction, refinement, and replacement--should be adhered to.

Electron microscopy of tissue adherent to explanted electrodes in dystonia and Parkinson's disease.

Deep brain stimulation (DBS) is used to treat a variety of severe medically intractable movement disorders, including Parkinson's disease, tremor and dystonia. There have been few studies examining the effect of chronic DBS on the brains of Parkinson's disease patients. Most of these post mortem studies concluded that chronic DBS caused mild gliosis around the lead track and did not damage brain tissue. There have been no similar histopathological studies on brains from dystonic patients who have undergone DBS. In this study, our objective was to discover whether tissue would be attached to DBS electrodes removed from patients for routine clinical reasons. We hoped that by examining explanted DBS electrodes using scanning (SEM) and/or transmission (TEM) electron microscopy we might visualize any attached tissue and thus understand the electrode-human brain tissue interaction more accurately. Initially, SEM was performed on one control DBS electrode that had not been implanted. Then 21 (one subthalamic nucleus and 20 globus pallidus internus) explanted DBS electrodes were prepared, after fixation in 3% glutaraldehyde, for SEM (n = 9) or TEM (n = 10), or both (n = 2), according to departmental protocol. The electrodes were sourced from two patients with Parkinson's disease, one with myoclonic dystonia, two with cervical dystonia and five with primary generalized dystonia, and had been in situ for 11 and 31 months (Parkinson's disease), 16 months (myoclonic dystonia), 14 and 24 months (cervical dystonia) and 3-24 months (primary generalized dystonia). Our results showed that a foreign body multinucleate giant cell-type reaction was present in all TEM samples and in SEM samples, prewashed to remove surface blood and fibrin, regardless of the diagnosis. Some of the giant cells were >100 microm in diameter and might have originated from either fusion of parenchymal microglia, resident perivascular macrophage precursors and/or monocytes/macrophages invading from the blood stream. The presence of mononuclear macrophages containing lysosomes and sometimes having conspicuous filopodia was detected by TEM. Both types of cell contained highly electron-dense inclusions, which probably represent phagocytosed material. Similar material, the exact nature of which is unknown, was also seen in the vicinity of these cells. This reaction was present irrespective of the duration of implantation and may be a response to the polyurethane component of the electrodes' surface coat. These findings may be relevant to our understanding of the time course of the clinical response to DBS in Parkinson's disease and various forms of dystonia, as well as contributing to the design characteristics of future DBS electrodes.